This is a competitive renewal application for a project that focuses on the systems-level organization of cholinergic innervation in the cerebral cortex of the monkey and human brain. The experiments proposed in this investigation have immediate implications for understanding the neurochemical substrate of memory and arousal, the pathogenesis of Alzheimer's disease and the cognitive potential of normal aging. We will continue to investigate the regional variations of cortical cholinergic innervation in the human cerebral neocortex, the comparative cytochemical signature of cholinergic neurons and their cortical projection patterns. Our recent studies showed that the human brain contains a vast network of acetylcholinesterases (AChE)-rich intra-cortical cholinoceptive neurons with an unusual and perhaps uniquely human developmental profile. The AChE-rich staining pattern of these neurons is not detectable until mid-to-late childhood, becomes established during early adulthood and maintains a remarkable stability into advanced senescence in non-demented individuals. Homologous neurons are not conspicuous in other animals species. These neurons may provide an anatomical substrate for development and plasticity during adulthood and perhaps even during healthy old age. These AChE-rich neocortical neurons appear to be depleted in Alzheimer's disease and may contribute to the genesis of cognitive deficits in patients with this condition. While these neurons represent a subset of cortical cholinoceptive cells, there are reasons for suggesting that their intense AChE activity is also associated with a host of non-cholinergic mechanisms that range from proteolysis to neural plasticity. One focus of this proposal aims to elucidate the cytochemical signature and developmental regulation of these neurons and their fate in the course of Alzheimer's disease. In a special sample of cognitively evaluated, non-demented senescent subjects we will determine if cognitive performance in old age is correlated with the density of these neurons and with the density of cortical cholinergic afferents. The methods to be employed include enzyme histochemistry, immunocytochemistry, in situ hybridization, electron microscopic histochemistry and axonal tracing (with horseradish peroxidase and fluorescent tracers) in the monkey brain.